Introduction
Angina is first and foremost a pain signal that originates from the heart to reach the brain. Typically, angina is triggered by myocardial ischemia. In addition to advanced coronary artery disease (CAD), microvascular dysfunction and vasospastic angina are well-described etiologies of myocardial ischemia resistant to medical therapy ( Fig. 27.1 ). Angina is often simplified as the mere reflection of myocardial ischemia resulting from an imbalance between oxygen supply and demand ( Fig. 27.2 ). However, the poor correlation between angina and the extent of coronary disease suggests that there is more than fixed epicardial coronary stenoses and oxygen deprivation to refractory angina. Angina becomes refractory when defective neurologic, psychogenic, or mitochondrial functions overlap with tissue ischemia to inappropriately maintain or enhance a persistent cardiac pain syndrome. Refractory anginas are therefore not a single disease but rather a mosaic of different systemic dysfunctions. Success in the treatment of refractory angina is unlikely to be achieved by addressing myocardial ischemia alone. Instead, the contemporary treatment of refractory angina also specifically addresses the neurogenic, psychogenic, and mitochondrial components of angina and cardiac pain ( Fig. 27.3 ).
Angina can be considered refractory for several reasons. Refractory angina is a complex interaction between symptoms, myocardial perfusion, and coronary anatomy ( Fig. 27.4 ). In some cases, patients with advanced CAD unsuitable for revascularization will experience persistent angina despite optimal doses of β-blockers, calcium-channel blockers (CCBs), and long-acting nitrates. In other cases, angina caused by microvascular dysfunction or vasospasm can go unrecognized before a proper diagnosis is finally made and an adequate treatment is implemented. In North America alone, up to 500,000 Canadians and more than 1.8 million Americans are estimated to have refractory angina. In Europe and the United States, it is estimated that between 5% and 15% of patients undergoing cardiac catheterization have refractory angina. Whereas the annualized mortality rates among patients with refractory angina range between 2% and 4%, the rates of ischemic endpoints (myocardial infarction [MI], stroke, cardiovascular rehospitalization, and revascularization) are approximately 50% in the 3 years following the diagnosis. The management of refractory angina is challenging, yet the condition is insufficiently studied and poorly covered by national practice guidelines. In this review, we discuss the pharmacologic, noninvasive, and interventional treatments of refractory angina in the context of past, present, and future innovations likely to influence how we treat refractory angina for the years to come.
Drug Therapy
The approach to refractory angina varies across different regions in the world, reflecting the local regulatory, organizational, and financial culture. The choice of an add-on drug when symptoms persist despite β-blockers, CCBs, or long-acting nitrates can seem empirical, but some principles are available to help guide the selection of a new drug, such as the blood pressure (BP) and heart rate, the lack of tolerance to nitrates, and the presumptive defective system responsible for refractory angina. In a 2015 systematic review and meta-analysis, Belsey et al. studied the relative efficacy of adding ranolazine, trimetazidine, or ivabradine to patients with angina, despite treatment with β-blockers or CCBs (no comparative study was available for nicorandil) ( Fig. 27.5 ). The results suggest that the addition of ranolazine, trimetazidine, or ivabradine can delay the ischemic threshold and does improve the control of angina. The use of traditional therapies—β-blockers, nitrates, and CCBs—has been reviewed elegantly by Husted and Ohman (see also Chapter 20 ). This section will focus on the evidence supporting the use of add-on antianginal drugs in patients with refractory angina.
Late Sodium Current Inhibitors
The tradition of treating angina with late sodium (Na) current inhibitors dates back to the 1960s when amiodarone was used in Europe. Nowadays, amiodarone is anecdotally used for refractory angina. Ranolazine, another late Na current inhibitor, has been extensively studied for stable angina with obstructive CAD and is considered in certain regions of the world to be on par with long-acting nitrates, ivabradine, or nicorandil as a second-line treatment after β-blockers or nondihydropyridine CCBs. Ranolazine is well suited for patients with persistent symptoms despite maximal tolerable doses of first-line antianginal agents, as its anti-ischemic effect is not related to heart rate or systemic BP lowering. The reason ranolazine is effective is debated, but likely involves an improved excitation-contraction coupling at the ventricular level and/or improved usage of oxygen at the mitochondrial level. In the diseased heart, the exaggerated influx of Na + and calcium (Ca 2+ ) in the myocytes impairs relaxation, which increases diastolic stiffness and begets ischemia by preventing adequate ventricular perfusion. Ranolazine inhibits the late sodium current in cardiomyocytes and prevents the accumulation of Na + ions in the myocytes, which in return prompts the sodium/calcium exchanger to expel calcium outside the myocytes to improve diastolic relaxation and coronary perfusion. In experimental models, ranolazine also inhibits the β-oxidation of fatty acid in mitochondria. This inhibition favors the oxidation of glucose, which requires less oxygen to yield similar amounts of adenosine triphosphate (ATP) production.
Ranolazine improves total exercise duration and increases ischemic threshold in patients with chronic stable angina. In the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial, ranolazine (750 mg or 1000 mg for 12 weeks) compared to a placebo on top of amlodipine, atenolol, or diltiazem increased total exercise duration and times to angina and to ischemia (1 mm ST-segment depression). Ranolazine decreased angina (by approximately one episode per week) and reduced the use of nitroglycerin. Similar results were observed in the Efficacy of Ranolazine in Chronic Angina (ERICA) trial, where ranolazine (500 mg twice daily) or placebo for 1 week, followed by ranolazine (1000 mg twice daily) or placebo for 6 weeks, was added to amlodipine. In the Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina (TERISA) trial, patients with type 2 diabetes mellitus and persistent angina despite one or two antianginal drugs experienced fewer angina episodes per week compared to placebo (3.8 vs. 4.3 episodes; p < 0.01) and consumed less sublingual nitroglycerin (1.7 vs. 2.1 doses; p < 0.01).
In a post hoc subgroup analysis of the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-Segment Elevation Acute Coronary Syndromes (MERLIN-TIMI 36) trial, 3565 participants who had a history of chronic angina prior to their index acute coronary syndrome experienced a significant reduction of the primary endpoint (cardiovascular death, MI, and recurrent ischemia) with ranolazine compared to placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75–0.97; p = 0.02). This reduction was mostly driven by a drop in the number of recurrent ischemic episodes (HR, 0.78; 95% CI, 0.67–0.91; p < 0.01). Similar results were observed when the analysis was restricted to patients with a history of moderate-to-severe angina before enrollment (HR, 0.75; 95% CI, 0.63–0.91; p < 0.01), but ranolazine had no impact on the occurrence of cardiovascular death or MI. This antiischemic effect persisted in a 30-day landmark analysis, for up to a year (HR, 0.80; 95% CI, 0.67–0.96; p = 0.02). Of note, patients in this substudy were treated with 2.9 antianginal agents on average over the entire duration of the follow-up.
The favorable results seen in the MERLIN subgroup analysis fueled the enthusiasm for the Ranolazine in patients with incomplete revascularization after percutaneous coronary intervention (PCI) (RIVER-PCI) trial, which assessed whether ranolazine 1000 mg twice daily was superior to placebo in 2651 participants with a history of chronic angina and incomplete revascularization post-PCI (residual lesions with diameter stenosis ≥ 50% in large coronary artery) at preventing the occurrence of ischemia-driven hospitalization with or without revascularization. Over a median follow-up of 643 days, the primary endpoint occurred in 345 participants (26%) assigned to ranolazine versus 364 participants (28%) assigned to placebo (HR, 0.95; 95% CI, 0.82–1.10; p = 0.48). Of note, the treatment effect of ranolazine for the primary endpoint remained the same in participants prescribed two to three anti-ischemic drugs, such as β-blockers, CCBs, or long-acting nitrates (HR, 1.04; 95% CI, 0.82–1.32; p interaction = 0.36). A safety subgroup analysis suggested that patients older than 75 years of age experienced higher rates of major adverse cardiovascular events (MACE) when given ranolazine compared to placebo. In this population, ranolazine provided no additional benefit to angina-related quality of life compared to placebo, as quality of life improved drastically in both groups following the PCI. Overall, patients enrolled in RIVER-PCI had a low angina burden at baseline and follow-up, leaving little room for the quantification of an improvement, once the effect of the index PCI and the regression to the mean were taken into account.
Ranolazine has been associated with favorable outcomes in small pilot studies of microvascular angina, and it was hypothesized that ranolazine could improve regional coronary in-flow in areas of myocardial ischemia. Bairey Merz et al. (2016) reported the results of a trial in participants with microvascular dysfunction but without obstructive CAD who were randomized to either short-term oral ranolazine 500 to 1000 mg twice daily for 2 weeks or placebo, then crossed over to the alternate treatment arm. The majority of patients were women treated with at least one antianginal drug, angiotensin converting enzyme inhibitors, and statins, and all participants had symptoms related to myocardial ischemia. Compared to placebo, ranolazine did not significantly improve the angina-related quality of life (measured by the Seattle Angina Questionnaire [SAQ]). In a mechanistic substudy, ranolazine failed to improve the myocardial perfusion reserve index (MPRI) measured by cardiac magnetic resonance imaging. One interesting finding was that the change in MPRI correlated with the change in SAQ score, suggesting that a modulation of microvascular dysfunction could lead to a new therapeutic avenue in patients with refractory angina. The suboptimal results in incompletely revascularized patients and those with microvascular disease might be a barrier to widespread use of ranolazine in this population.
Due to pharmacologic interaction, ranolazine should not be used concomitantly with nondihydropyridine CCBs, ketoconazole, or macrolide antibiotics.
Partial Fatty Acid Oxidation Inhibitors
Trimetazidine
Trimetazidine (TMZ) is frequently presented as the archetype of partial fatty acid oxidation (pFOX) inhibitors. TMZ is proposed to modulate the mitochondrial metabolism by blocking the long-chain 3-ketoacyl-CoA thiolase (KAT), a key enzyme in the β-oxidation of fatty acids. This blockade is thought to shift the mitochondrial substrate utilization toward glycolysis, which requires 10% to 15% less oxygen than the oxidation of fatty acid to yield the same energy. A partial inhibition of fatty acid oxidation has the potential to prevent the intracellular accumulation of lactate and protons, both of which are associated with impaired contraction–relaxation coupling in ischemic myocytes. Although appealing, this presumptive mechanism of action is challenged by evidence suggesting that TMZ does not alter metabolic substrate oxidation in the human cardiac mitochondria but rather acts via an unidentified intracardiac mechanism, possibly involving the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and extracellular signal-related kinase (ERK) signaling pathway, and the activation of p38 mitogen-activated protein kinase and Akt signaling.
In the TRIMetazidine in POLand (TRIMPOL II) trial, 426 participants with stable CAD and an abnormal treadmill stress test despite metoprolol 50 mg twice daily were randomized to either TMZ (20 mg three times daily over 12 weeks) or matching placebo. TMZ markedly improved the time to ST-segment depression compared to placebo (+ 86 s vs. + 24 s; p < 0.01). Likewise, TMZ reduced the weekly angina count (– 1.9 episodes vs. – 0.9 episode; p < 0.01).
In a recent meta-analysis of 1628 participants involved in 13 randomized trials from 1997 to 2013, TMZ in addition to antianginal medication was shown to be superior to antianginal medications at reducing the weekly angina count (weighted mean difference [WMD] = –0.95 episode; 95% CI, –1.30 episode to –0.61 episode; p < 0.001), the weekly nitroglycerin use (WMD = –0.98; 95% CI, –1.44 to –0.52; p < 0.001), and the time to 1-mm ST-segment depression (WMD = 0.30; 95% CI, 0.17 to 0.43; p < 0.001). Of note, only four of the trials included in the pooled analyses were appropriately blinded. These results contradict a previous meta-analysis that detected no benefit. Importantly, TMZ has not been associated with a reduction in mortality or cardiovascular events. TMZ is associated with adverse extrapyramidal reactions such as restless leg syndrome and parkinsonism.
In summary, data supporting the use of TMZ are conflicting and further clinical trials are required. The European Medicines Agency (EMA) has restricted the use of TMZ as add-on therapy for patients who remain symptomatic or are intolerant to first-line antianginal treatments. The efficAcy and safety of Trimetazidine in Patients with angina pectoris having been treated by Percutaneous Coronary Intervention (ATPCI) trial (EudraCT Number: 2010-022134-89) is examining the efficacy of TMZ in patients with post-PCI angina. Results of this large trial are expected in 2017.
Perhexiline Maleate
Perhexiline is one of the oldest known antianginal drugs and was extensively studied in the 1970s before β-blockers and CCBs became mainstream therapies. Despite its seeming efficacy, perhexiline was removed from the market in several countries due to cases of hepatotoxicity and neurotoxicity with chronic therapy, predominantly explained by drug accumulation in slow CYP2D6 metabolizers.
Perhexiline is a pFOX inhibitor that modulates mitochondrial metabolism by inhibiting the enzymes carnitine O -palmitoyltransferase (CPT) 1 and 2, which are responsible for the transfer of free fatty acids from the cytosol to the mitochondria. These effects are systemic and not limited to the heart. Similar to TMZ, perhexiline is thought to shift the mitochondrial substrate utilization toward glucose oxidation, which is more energy efficient as it requires less oxygen to produce the same amount of ATP. Based on stoichiometric models, an approximate 11% to 13% increase in oxygen efficiency would be expected by entirely blocking fatty acid metabolism in favor of an exclusive carbohydrate metabolism. In practice, a predominant mitochondrial carbohydrate oxidation has been reported to be at least 30% to 40% more efficient than free fatty acid oxidation. Animal metabolomic studies suggest that perhexiline may also favor lactate and amino acid uptake by the heart. Perhexiline is also a weak L-type CCB, a sodium channel blocker, and a vasodilator, but these possible antianginal properties have never been fully delineated.
In a systematic review counting 26 small, randomized, mostly cross-over, double-blind, controlled trials and 696 participants, perhexiline monotherapy was associated with a consistent reduction in the frequency of angina attacks and nitroglycerin consumption, although there were concerns around the quality of reporting of the available trials. In a small, double-blind, controlled crossover trial ( n = 17 participants), perhexiline was associated with a greater proportion (65%) of responders (measured by a reduction in angina as measured in a dedicated diary over 3 months) compared with placebo (18%, p < 0.05) in patients with refractory angina, despite the combination of β-blockers, nitrates, and CCBs. Likewise, all patients improved their performance on a treadmill stress test, compared with none when treated with placebo. Five of 17 (29%) patients developed significant side effects despite plasma concentration monitoring, including four cases of transient ataxia. Similar findings were reported in patients treated with adequate β-blockade. Of note, few trials have tested the efficacy of perhexiline at dosages deemed to be safe in most patients (100 to 200 mg/day). In a large 5-year retrospective series from two centers, perhexiline was associated with angina relief in most patients with otherwise refractory symptoms. However, the treatment was discontinued in 20% of patients due to side effects or out of safety concerns, despite careful therapeutic drug level monitoring.
Therapeutic plasma monitoring opens the door to the personalized perhexiline administration in selected cases to avoid excessive drug accumulation. Short-term dizziness, nausea, vomiting, lethargy, and tremors are acute adverse effects observed with perhexiline. Perhexiline may be safely started at a dose of 100 mg twice daily and monitored at 1, 4, and 8 weeks to maintain plasma concentrations between 0.15 and 0.60 mg/L. Perhexiline has been associated with occasional QT interval prolongation, especially in patients with K + -channel mutations (KCNQ1), and additional safety information will be required before it can be widely recommended in clinical practice. The genetic screening of allelic variants associated with slow cytochrome P450 2D6 hydroxylation may obviate the need for plasma monitoring in the future. Mutations in CYP2D6 are present in 7% to 10% of Caucasians versus 2% of African Americans and less than 1% in Chinese and Japanese populations. Perhexiline is used for refractory angina in Australia and New Zealand.
Mildronate
Mildronate (better known as meldonium) has recently drawn a lot of attention after the suspension of a high-profile tennis player for doping. Mildronate indirectly acts as a pFOX inhibitor by blocking the enzyme γ-butyrobetaine hydroxylase (GGBH), which catalyses the biosynthesis of carnitine. Carnitine is essential for the transfer of long-chain fatty acids across the mitochondrial inner membrane for oxidation and ATP synthesis. Mildronate also inhibits the activity of carnitine acetyltransferase (CAT), an enzyme that regulates the level of acetyl coenzyme A (acetyl-CoA) in the mitochondria, which plays a key role in several aspects of intermediary metabolism, including the oxidation of free fatty acids. In the phase II dose-finding MILSS (a dose-dependent improvement in exercise tolerance in patients with stable angina treated with mildronate) trial, 512 patients with chronic stable Canadian Cardiovascular Society (CCS) class II–III angina, despite β-blockers (> 94%), long-acting nitrates (> 70%), or CCB (35–50%), were blindly randomized to either mildronate (one of four doses: 100 mg, 300 mg, 1000 mg, or 3000 mg) or placebo for 12 weeks. Mildronate resulted in a dose-related improvement in total exercise duration, as measured on a standard bicycle ergometer. Patients assigned to the 1000-mg dose (given as 500 mg twice daily) obtained the best effect compared to placebo (+35.2 s ± 53.3 s vs. –7.1 s ± 81.8 s, p = 0.002). No significant difference in the time to onset of angina was noted between the groups. Mildronate was developed in the former Soviet Union for the treatment of MI and stroke and has never been approved elsewhere. Mildronate is conceptually interesting for refractory angina, but insufficient evidence exists to support its use in clinical practice.
Nitric Oxide Donors
Nicorandil
Nicorandil is a coronary vasodilator with cardioprotective properties. The nicotinamide-nitrate ester acts as an ATP-sensitive potassium channel (KATP) opener at the mitochondrial level to mimic ischemic preconditioning and prepare the myocytes against injury. Similar to long-acting nitrates, nicorandil is a nitric oxide (NO) donor which directly vasodilates coronary arteries. Unlike nitrates however, nicorandil does not impair endothelial function and is not associated with tachyphylaxis and tolerance. Besides vasodilation, some evidence suggests that nicorandil may also have an intrinsic analgesic activity and may reduce the nociceptive response to angina. Likewise, nicorandil may also improve the myocardial fatty acid metabolism. For these reasons, nicorandil is conceptually appealing in patients with severe angina and advanced CAD, and in patients with vasospastic angina.
Nicorandil exerts effects similar to β-blockers, long-acting nitrates, and CCBs in patients with stable CAD with no other background treatment. The Impact Of Nicorandil in Angina (IONA) trial compared nicorandil versus placebo in 5126 patients with chronic angina despite nitrates (87%), β-blockers (57%), or CCBs (55%). Nicorandil reduced the combined occurrence of cardiovascular death, nonfatal MI, or unplanned admissions to hospital for chest pain (13.1% vs. 15.5%; p = 0.02) and confirmed the cardioprotective effect of nicorandil in patients with CAD. From this trial, no data were reported on the effect of nicorandil on angina symptoms or quality of life. At 6 months, 29.6% of patients assigned to nicorandil discontinued their study drug due to adverse effects, compared with 19.5% in patients assigned to placebo. No study has yet described the potential merit of nicorandil in patients with refractory angina despite classical antianginal drugs administered at maximal tolerable dose.
The European Society of Cardiology (ESC) practice guidelines recommend nicorandil as a second-line treatment for the relief of angina/ischemia (class IIa indication), on par with long-acting nitrates, ivabradine, and ranolazine, according to heart rate, BP, and tolerance. Surprisingly, no studies have been reported that describe the efficacy of nicorandil in an add-on role in angina. Nicorandil is only available by special-access programs run by regulatory agencies in Canada and the United States. As is the case with all NO donors, nicorandil can cause headaches and hypotension. Not infrequently, nicorandil can induce oral, anal, or gastrointestinal ulceration, which typically subsides upon drug discontinuation.
Molsidomine
Molsidomine is similar to long-acting nitrates, both in terms of mechanism of action and efficacy. Molsidomine mediates its effect via NO and increases myocardial perfusion by vasodilating the coronary arterial system, and reduces oxygen demand by increasing the peripheral venous capacitance, cardiac preload, and wall tension. Like long-acting nitrates, molsidomine could also be associated with tachyphylaxis and tolerance.
Molsidomine has not been tested in refractory angina. Two different formulations of molsidomine (8 mg twice daily vs. 16 mg daily) were compared to a placebo in a randomized trial of 533 patients with new onset angina pectoris where β-blockers, CCBs, and long-acting nitrates were prescribed. Both formulations of molsidomine were better than placebo at reducing the weekly angina count (2.3 ± 3.2 episodes vs. 3.8 ± 3.7 episodes, p < 0.001) and reducing the use of short-acting nitrates, and resulted in a significantly improved total exercise duration. In the 2015 Effect of Molsidomine on the Endothelial Dysfunction in Patients with Angina Pectoris (MEDCORE) randomized controlled trial (RCT), molsidomine 16 mg once a day for 12 months as an add-on treatment to best of care medical therapy failed to improve endothelial dysfunction over placebo in patients who underwent a PCI for stable angina pectoris. In real-world settings, molsidomine is well tolerated with only 9.1% of patients treated over the course of 1 year reporting drug-related adverse events (mostly headaches and hypotension). Given the lack of evidence specific to refractory angina and the lack of safety data, molsidomine should probably be used cautiously in this population.
l -Arginine
The amino acid l -arginine is transformed by the NO synthases into NO, which mediates the endothelium-dependent vasodilatation. Supplemental oral l -arginine (1 g TID) improves small-vessel coronary endothelial function in healthy individuals. Whereas l -arginine has been shown to be better than a placebo at improving the total exercise duration on treadmill stress test in patients with stable CAD, it has not been adequately investigated in refractory angina. In a small factorial trial, Ruel et al. suggested that l -arginine (6 g per day) may potentiate the effect of vascular endothelial growth factor (VEGF)-165 plasmid DNA in patients with advanced CAD. Participants who received the combination of VEGF-165 plasmid DNA and l -arginine had improved anterior wall perfusion on positron emission tomography.
I (f) Current Inhibitors
Ivabradine selectively inhibits the I (f) current which regulates the intrinsic chronotropic properties of the pacemaker cells in the sinoatrial node and lowers the heart rate. Ivabradine does not reduce BP nor does it exert a negative effect on the excitability of the heart and the conductive properties of the atrioventricular (AV) node.
In the Efficacy and Safety of Ivabradine on Top of Atenolol in Stable Angina Pectoris (ASSOCIATE) trial, ivabradine up to 7.5 mg twice daily for 4 months was superior to placebo at improving the total exercise duration compared to placebo (+24.3 s ± 65.3 s vs. 7.7 s ± 63.8 s; p < 0.001) in patients with persistent angina despite atenolol 50 mg daily. In small pilot trials performed in patients suffering microvascular angina, ivabradine (5 mg twice daily) has been superior to placebo at improving angina-related quality of life. Ivabradine did not improve cardiovascular outcomes in patients with stable CAD and left ventricular systolic dysfunction. However in the ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL) trial, the subgroup of participants who had limiting angina at baseline experienced a 24% reduction in cardiovascular death and hospitalization for MI or heart failure (HF). The majority of these patients were treated with β-blockers and long-acting nitrates.
In the Study assessInG the morbidity-mortality beNefits of the I (f) inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY) trial, a dose of ivabradine adjusted to reach a heart rate of 55 to 60 beats per minute (bpm) on top of guideline-directed medical therapy was not superior to placebo at improving the occurrence of cardiovascular death or MI in 19,102 patients with stable CAD and a heart rate of 70 bpm or greater (6.8% vs. 6.4%, respectively; HR, 1.08; 95% CI, 0.96–1.20; p = 0.20; median follow-up of 27.8 months). In the subgroup of patients with symptomatic angina (CCS class II or higher), a greater proportion of ivabradine-treated patients experienced an improvement in their CCS angina class (24.0% vs. 18.8%, p = 0.01). Despite these favorable findings, ivabradine was associated with a small yet significant increase in cardiovascular death and MI (HR, 1.18; 95% CI, 1.03–1.35; p interaction = 0.02) in this subgroup. Based on these results, caution has been advised regarding the prescription of ivabradine in patients with angina without HF. Ivabradine might be considered in individuals with a heart rate of 70 bpm or greater who do not tolerate doses of β-blockers or when CCBs are contraindicated. Ivabradine has also been associated with new-onset atrial fibrillation, bradycardia, and blurred vision.
Miscellaneous Pharmacologic Agents
Allopurinol
Allopurinol reduces oxygen wastage by inhibiting xanthine oxidase, an enzyme involved in the oxidative stress response. Allopurinol may also improve endothelial function in patients with CAD. In a small cross-over randomized trial, participants with stable CAD assigned to allopurinol (300 mg twice daily) did better than those assigned to placebo at improving their time to 1-mm ST-segment depression (+58 s; 95% CI, 45–77 s) and their time to chest pain (+43 s; 95% CI, 31–58 s) on exercise treadmill test. The trial lacked power to detect a variation in angina burden, quality of life, or clinical outcomes. These findings are yet to be replicated independently. Allopurinol is cheap and could represent an interesting option in some regions of the world. At high dose (600 mg daily), toxic effects are possible and close monitoring is advised in patients with chronic renal failure.
Intermittent Thrombolytic
Intermittent thrombolytic is of historic importance as the case example of the principle of improved blood rheology to treat myocardial ischemia. Poiseuille’s law indicates that a reduced blood viscosity should translate into a superior flow in the coronary microcirculation. Because fibrinogen is a major determinant of plasma viscosity, its reduction by fibrinolysis should theoretically translate into reduced myocardial ischemia and angina. In a small randomized trial, a high dose of intermittent urokinase was better than a lower dose (500,000 IU vs. 50,000 IU IV, three times a week over 12 weeks) at improving the weekly angina count.
Testosterone and Estrogen
Testosterone administration has been linked to an increased risk of adverse cardiovascular events. However, it has been hypothesized that testosterone might improve the endothelium-dependent vasodilation of coronary arteries. In small clinical studies, testosterone administration has been linked to improved angina threshold in men with chronic stable angina. The recent US Food and Drug Administration (USFDA) restrictions on testosterone replacement therapy reinforce the notion that it should probably be avoided in high-risk patients until additional evidence becomes available. Similar to testosterone, estrogen has been investigated in patients with stable angina despite concern about increased cardiovascular risk in healthy postmenopausal US women. Estrogen has been linked to improved endothelial function. Estradiol-drospirenone hormone replacement therapy has been shown to improve myocardial perfusion reserve in postmenopausal women with angina pectoris. In a small randomized double-blind trial, estradiol plus norethindrone acetate therapy for 16 weeks outperformed placebo at improving the total exercise duration (+32.7 s vs. 2.5 s, p < 0.05) and the time to 1-mm ST-segment depression (+99.1 s vs. 22.9 s, p < 0.05) compared to placebo in 74 Chinese postmenopausal women with established CAD. Neither testosterone nor estrogen supplementation has been properly investigated in patients with advanced CAD and refractory angina.
Omapatrilat
The vasopeptidase inhibitor omapatrilat inhibits both the angiotensin-converting enzyme (ACE) and the neutral endopeptidase (NEP). NEP catalyses the breakdown of natriuretic peptides (atrial natriuretic peptide, brain-derived natriuretic peptide, and C-type natriuretic peptide) and of bradykinine. The natriuretic peptides antagonize the sympathetic nervous system and the renin-angiotensin-aldosterone system, which might be beneficial in patients with significant myocardial ischemia. The concept of NEP inhibition in patients with chronic angina pectoris was tested in a proof-of-principle study where 348 participants with stable β-blocker monotherapy were blindly randomized to either omapatrilat (titrated up to 80 mg daily over 4 weeks) or matching placebo. Participants assigned to omapatrilat significantly improved their total exercise duration in an exercise treadmill test compared to those assigned to placebo (76.6 s ± 84.2 s vs. 28.7 s ± 82.2 s, difference from baseline, p < 0.001). Likewise, omapatrilat also resulted in a significant improvement in the time to onset of 1-mm ST-segment depression (84 s ± 7 s vs. 34 s ± 7 s, p < 0.001). The anti-ischemic effect of omapatrilat was likely mediated by a blunting effect in systolic BP, as the rate–pressure product at peak exertion was lower in patients treated with the active drug compared to placebo (Δ – 609 ± –1254 to 36, p = 0.06). Omapatrilat was not approved by the USFDA due to concern over angioedema, possibly caused by an excessive bradykinin accumulation resulting from NEP inhibition. Sacubitril, a neprilysin neutral peptidase inhibitor combined with an angiotensin receptor antagonist to minimize angioedema, yielded favorable outcomes in patients with HF in the Prospective comparison of AR (angiotensin receptor) and NI (neprilysin inhibition) with ACE Inhibition to Determine Impact on Global Mortality and morbidity in Heart Failure (PARDIGM-HFT) trial. The results are likely to revive the interest in the concept of broad vasopeptidase inhibition in angina.
Traditional Chinese Medicine
Traditional Chinese herbal medicines may be a valuable option to treat angina. Dantonic (T89) is a water extract of Danshen (Radix et Rhizoma Salviae Miltiorrhizae) and Sanqi (Radix et Rhizoma Notoginseng) combined with Bingpian (Borneol) to enhance absorption. Dantonic is currently being tested in a formal USFDA phase III placebo-controlled trial for efficacy in patients with CCS class II or III stable angina despite a β-blocker or a CCB and short-acting nitroglycerin. Enrollment ended in 2015 and results are expected in late 2016 (NCT01659580). Several mechanisms of action have been proposed to explain how dantonic may relieve angina, including improved blood rheology and antioxidant properties. Other than Danshen and Sanqi, several traditional Chinese medicines have been tested in patients with angina, with inconsistent results. Other nontraditional methods such as herbal acupoint application and acupuncture have been advocated but have not been adequately tested.
Interventional Therapies
Chronic Total Occlusions
Chronic total occlusions (CTOs), once the last frontier of interventional cardiology, are now routinely recanalized in the hope of improving long-term outcomes and symptoms. Current practice guidelines recommend that the percutaneous recanalization of CTOs should be considered in patients with symptoms or in the presence of objective evidence of viability/ischemia in the territory of the occluded artery. The appropriate use criteria for coronary revascularization deem the recanalization of an isolated CTO appropriate if, despite maximal anti-ischemic medical therapy, moderate symptoms persist (angina CCS II or higher) and high-risk features are present on noninvasive testing, or severe symptoms persist (angina CCS III or more) with at least moderate risk features on noninvasive testing. Pooled estimates from observational studies consistently report a lower mortality (odds ratio [OR], 0.52; 95% CI, 0.43–0.63), a lower risk of MACE (OR, 0.59; 95% CI, 0.44–0.79), and a lower need for subsequent coronary artery bypass graft (CABG) (OR, 0.18; 95% CI, 0.14–0.22) in successfully recanalized CTO patients, compared to patients with failed recanalization. It is important to note that these observational comparisons of successful versus failed CTO PCIs are not sufficient to demonstrate the efficacy of this procedure on clinical outcomes.
The association between CTO PCIs and angina also remains controversial. In a recent meta-analysis with nine nonrandomized studies and 2536 patients covering 25 years, a successful CTO PCI was associated with a reduction in the risk of residual angina (OR, 0.38; 95% CI, 0.24–0.60) compared to a failed CTO PCI. Few of these observational studies used appropriate research tools to quantify post-PCI angina, and a sizable portion of the evidence originates from the pre-stent era. Olivari et al. reported a reduction in ischemic burden in patients with a successful CTO PCI, as they were more likely to have a normal exercise treadmill time at 12 months than were those with a failed CTO PCI (73% vs. 47%; p < 0.001). Jolicoeur et al. failed to show an improvement in the rates of self-reported angina (20% vs. 24%; p = 0.50) and good-to-excellent quality of life (73% versus 68%; p = 0.52) 6 months after a successful and a failed CTO PCI, respectively. Borgia et al. used the SAQ in 302 consecutive patients who underwent an attempt of CTO PCI at their center. Overall, a successful CTO PCI was associated with less limitation in physical activity and improved treatment satisfaction (53%), compared to 31% of patients with a failed CTO PCI. Importantly, more than 75% of patients in the former group reported symptomatic improvement at late follow-up.
CTO PCIs are complex interventions with the potential for microvascular plugging and distal bed embolization. In addition, patients with a CTO may have microvascular dysfunction in addition to epicardial disease that can persist despite a successful recanalization. In a series of 120 consecutive patients with a successfully recanalized CTO, microvascular dysfunction quantified by coronary flow velocity reserve (CFVR) was measured immediately after the index PCI and repeated 5 months later. On average, CFVR increased from 2.01 ± 0.58 at baseline to 2.50 ± 0.79 at follow-up ( p = 0.001). Microvascular dysfunction, which in that study was defined as a CFVR < 2.0, was observed in 46% of patients after recanalization and persisted in 17% at follow-up. Diabetes mellitus was a major determinant of persistent microvascular dysfunction.
There are no reported RCTs comparing CTO PCI to medical therapy, but at least two large trials are under way that are expected to provide important new data to inform the field—the Drug-Eluting Stent Implantation Versus Optimal Medical Treatment in Patients with Chronic Total Occlusion (DECISION CTO) trial ( n = 1300; NCT01078051) and the European Study on the Utilization of Revascularization Versus Optimal Medical Therapy for the Treatment of Chronic Total Coronary Occlusions (EURO-CTO) trial (NCT01760083).
Reduction of the Coronary Sinus
Before CABGs were routinely performed to treat angina, Beck and Leighninger proposed in the mid-20th century a surgery to restrict the venous drainage of the heart. The surgical narrowing of the coronary sinus (CS) was meant to favor a redistribution of the oxygenated blood into ischemic territories and was associated with a remarkable efficacy. A contemporary exploitation of this concept is the percutaneous reduction of the CS in patients with refractory angina unsuitable for revascularization. The phase II Coronary Sinus Reducer for Treatment of Refractory Angina (COSIRA) trial tested a balloon-expandable stainless steel hourglass-shaped metal stent called Reducer in patients with severe refractory angina due to advanced CAD unsuitable for revascularization. The device is implanted in the CS and creates a focal narrowing leading to an increase in CS pressures ( Fig. 27.6A ). In COSIRA, the Reducer was associated with a greater proportion of patients who improved by two CCS angina classes, compared to a blinded sham implantation (35% vs. 15%, p = 0.02).
Other interventions that modulate the CS pressure have been investigated, including the pressure-controlled intermittent coronary sinus occlusion (PICSO) in diverse ischemic settings, including during CABG and STEMI. How exactly the modulation of the CS pressure can relieve angina is not clear. Experimental evidence supports the notion that pressure elevation in the CS favors the recruitment of collateral flow toward the ischemic myocardium. A reduction of the coronary sinus is thought to apply a backward pressure to the venules and capillaries, which is thought to recruit arterioles and preferentially reduce the resistance to flow in the ischemic subendocardium (see Fig. 27.6B ).
In the healthy heart, the subendocardium is preferentially perfused during stress due to a physiologic vasoconstriction in the subepicardial layers. In the diseased heart, this compensatory mechanism is impaired, leading to a relative hypoperfusion of the subendocardium (see Fig. 27.6B , red arrows) and a proportional reduction in venous drainage (see Fig. 27.6B , purple arrows ). In addition, any increase in the left ventricular (LV) end-diastolic pressure (LVEDP) further compromises the flow in the subendocardial capillaries. In response to a narrowing of the CS, the backward pressure applied to the venules and capillaries (see Fig. 27.6B , green arrows ) is thought to recruit arterioles and preferentially reduce the resistance to flow in the ischemic subendocardium, which improves perfusion, contractility, and reduces LVEDP and breaks the vicious cycle of ischemia.
Therapeutic Angiogenesis
Protein and Gene Therapy
Recombinant growth factors and gene therapy have been tested in the hope of enhancing the natural angiogenesis process in patients with advanced CAD. The intracoronary delivery of angiogenic proteins VEGF and fibroblast growth factor (FGF) both failed to meet their primary endpoint (total exercise duration) in large, randomized, placebo-controlled trials, although there were positive secondary endpoints. To address the lack of efficacy of short half-life protein therapy, cardiac gene therapy has been developed in the hope of allowing a sustained expression of angiogenic factors in ischemic territories. The efficacy signal observed with the intracoronary (IC) delivery of an adenovirus encoding FGF5 (Ad5FGF) in the early-phase Angiogenic Gene Therapy (AGENT) and AGENT-II trials prompted the phase III trials AGENT-III and AGENT-IV, which compared different doses of Ad5FGF-4 (up to 1 × 10 10 viral particles) to placebo. A pooled analysis of both trials ( n = 532 participants) revealed no significant change in total exercise duration 12 weeks after therapy with Ad5FGF-4 compared to placebo. Post-hoc analyses suggested a substantial exercise benefit in high-risk patients (aged > 55 years, angina class III or higher, and baseline exercise duration inferior to 300 s). Likewise, a significant beneficial effect was observed in women, who improved their total exercise duration and functional class. These findings await prospective validation in a dedicated trial. The direct intramyocardial injection of VEGF-165 gene therapy in patients with advanced CAD failed to improve the perfusion of ischemic myocardium in two distinct placebo-controlled trials. Other smaller, open-label trials have reached discordant results. The ongoing KAT301 trial testing endocardial VEGF-D gene therapy in patients with advanced CAD is likely to bring additional information to the discussion (NCT01002430). The future of gene-based therapeutic angiogenesis may lie in the use of multiple growth factor therapies embedded in biologic scaffolds.
Cell Therapy
Besides the potential direct dependent of collaterals, cell therapy is hypothesized to locally release proangiogenic cytokines that promote angiogenesis and improve blood supply to the ischemic myocardium. Cell therapy is also thought to favorably alter myocardial function, reduce apoptosis, and recruit both resident and circulating stem cells. Some evidence links cell therapy to reduced mortality and improved functionality in the long term in patients with ischemic heart disease ( Fig. 27.7 ). At this time, fewer than 10 randomized placebo-controlled trials have been conducted to assess cell therapy specifically in patients with intractable or refractory angina. A pooled analysis of 331 participants enrolled in five phase I/II trials has suggested that cell therapy (either autologous CD34+ cells or bone marrow mononuclear cells) may be better than a placebo delivery at decreasing the weekly angina count (by seven episodes per week; 95% CI, 1–13; p = 0.02), at increasing the total exercise duration on a stress test (by 61 s; 95% CI, 18–104 s; p = 0.005), and at reducing the odds of experiencing an MI (OR = 0.37; 95% CI, 0.14–0.95; p = 0.04).
Autologous CD34+ cells are endothelial progenitors isolated from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood, which may be partially effective. Wang et al. assessed the efficacy of autologous CD34+ cells (mean dose of 5.6 × 10 7 cells) compared to a placebo transfused in the coronary arteries of 112 patients with refractory angina. At 6 months, the weekly angina count was significantly reduced in patients treated with autologous CD34+ cells (–15.6 ± 4.0 episodes) compared with placebo (–3.0 ± 1.2 episodes; p < 0.01). Likewise, Lee et al. found that the intracoronary transfusion of CD34+ cells was superior to a sham delivery at improving left ventricular ejection fraction (LVEF), possibly via an improved neovascularization. However, exercise tolerance and symptoms remained similar in both groups. The largest experience is with intramyocardial CD34+ cell therapy that included phase I/IIa, IIb, and III trials. In the phase IIb ACT34+ trial, intramyocardial CD34+ cells (1 × 10 5 cells per kg) improved weekly angina count compared to a sham placebo intervention (–6.8 ± 1.1 episodes vs. –10.9 ± 1.2 episodes; p = 0.02). Similar results were found for total exercise duration in a treadmill stress test (139 s ± 115 s versus 69 s ± 122 s; p = 0.01). CD34+ cell therapy was associated with a persistent improvement in angina at 2 years. These favorable results prompted the phase III Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects with Refractory Angina (RENEW) trial, which stopped after 112 participants (of the 444 initially planned) had been randomized due to a financial decision by the sponsors. Although underpowered, the results seen in RENEW were consistent with those observed in the phase II trial.
In an uncontrolled study, autologous mesenchymal stromal cells (MSCs) injected directly into the ischemic myocardium of patients with advanced CAD have been associated with improved total exercise duration and angina class up to 3 years. In a phase I/II RCT, CD133 cells injected directly into the myocardium reduced significantly the monthly angina count (−8.5 episodes; 95% CI, −15.0 episodes to −4.0 episodes) and the angina functional class compared to no cell therapy. Mechanistic studies even suggest that repeating the intramyocardial injection of bone marrow mononuclear cells in previous responders can further improve ischemia and relieve angina. Although the results are promising, cell therapy is an investigational product and its use should remain confined to formal clinical investigations.
Neuromodulation
The heart muscle does not ache. The genesis of angina is a complex neurogenic phenomenon that involves both the receptors of the sympathetic and vagal afferent pathways. How ischemia triggers a pain signal is still unclear and likely results from a multitude of substances such as lactates, adenosine, bradykinin, and potassium that irritates the chemosensitive endings of unmyelinated (C) fibers and of myelinated (Aδ) fibers embedded in the myocardium. Sympathetic fibers coalesce toward the cardiac sympathetic afferent nerve and reach the paravertebral sympathetic ganglia, which form the sympathetic cervical chain, including the stellate ganglia. Excitation of the sympathetic afferent fibers at the myocardial level stimulates the spinothalamic tract cells in the cervico-thoracic spinal segments and mediates the angina located in the chest and arm. Excitation of the vagal afferent fibers mediates the angina located in the neck and jaw.
The nervous system has several points of convergence where specific information transits (such as the cardiac pain impulse). In the peripheral nervous system, some of these points are readily accessible for targeted interventions, such as the stellate ganglia or the spinal tract. However, because of the duplicity of the afferent pathways involved in the transmission of noxious cardiac signals, it is unlikely that single interventions—however targeted they may be—may entirely suppress angina. The cardiac nociceptive signal is also processed centrally by the thalamus, which plays the role of a gate, and the cortex. The latter seems to be amenable to modulation by interventions such as self-management training or selective serotonin-reuptake inhibitor (SSRI).
Cardiac neuromodulation involves the deception or the interruption of a nociceptive signal using chemical, electrical, or mechanical means that can be applied at any level in the transmission pathway from the heart to the central nervous system. Conceptually, neuromodulation is appealing for the relief of cardiac pain with a prominent neurogenic component, as is the case with inappropriate cardiac pain perception. Because neuromodulation can potentially alter any cardiac pain signal, regardless of the pathophysiology, neuromodulation may be useful in patients with refractory angina. Neuromodulation may also favorably alter the sympathetic afference responsible for coronary artery vasoconstriction. The evidence available to support the various possible declinations of neuromodulation is still suboptimal.
Spinal Cord Stimulation
Spinal cord stimulation (SCS) achieves electroanalgesia after a multipolar electrode is positioned in the epidural space near the dorsal column between the C7 and T4 vertebrae where the cardiac afferent sympathetic fibers synapse with second-order sensory neurons in the dorsal horns. The electrodes stimulate the dorsal horn and blur the transmission of the nociceptive impulse en route toward the spinothalamic tract. The main effect of SCS is to replace the unpleasant experience of angina with more tolerable precordial paresthesias. How SCS mediates its effect is not entirely elucidated, but it has been hypothesized to change the dorsal horn chemistry by promoting the release of γ-aminobutyric acid (GABA) and of β-endorphins, which antagonizes the descending inhibitory pathways, otherwise known to favor the transmission of nociceptive impulses. In addition to an analgesic effect, SCS may have an anti-ischemic effect by downmodulating the autonomic nervous system through a partial sympatholysis with ensuing vasodilation and improved flow in the coronary microcirculation. Although appealing, this association has not been consistent in the literature.
SCS has been tested in several small clinical trials against various comparators, such as optimal medical therapy, transmyocardial laser, and even CABG. The available trials were frequently interrupted prematurely due to poor enrollment, and were unblinded due to the obvious paresthesia caused by SCS once activated. A meta-analysis with seven RCTs and 270 patients suggested that SCS significantly improved the total exercise duration (standardized mean difference [SMD] 0.76; 95% CI 0.07–1.46; p = 0.03) and health-related quality of life (SMD 0.83; 95% CI, 0.32–1.34; p = 0.001). SCS in patients with advanced CAD has also been associated with an improvement in LVEF. The potential benefits of SCS are now being explored in patients with chronic HF, but the efficacy is uncertain. Small studies have suggested that SCS plus medical therapy is cost-effective despite the higher costs at the initiation of therapy. Randomized trials from 2015 and real-life observational studies support these findings.
An interesting variation to SCS is subcutaneous electrical nerve stimulation (SENS) where two multipolar electrodes are subcutaneously implanted in each side of the sternum at the level where the retrosternal pain radiates during an angina episode. SENS targets subcutaneous nerve endings and has been associated with improved angina and reduced sublingual nitrate consumption in a small study.
Based on moderate-quality evidence, most cardiology practice guidelines weakly recommend SCS, suggesting it may be considered to improve exercise capacity and quality of life in patients with refractory angina. When considered, SCS requires a multidisciplinary approach including a discussion regarding the safety and timing of stopping oral anticoagulants and antiplatelet agents to avoid epidural bleeding. SCS is generally performed as a minor surgical procedure under local anesthesia. SCS elevates the angina threshold, but breakthrough angina episodes are still possible despite active stimulation, such as when the signal is particularly intense. The concerns around silencing life-threatening ischemic episodes are therefore unsubstantiated. Interactions between SCS pulse generators and implantable defibrillators are possible and warrant proper surveillance.
Cardiac Sympathectomy
In addition to allowing the retropropagation of cardiac nociceptive impulses to the brain, the sympathetic nervous system can cause myocardial ischemia directly by favoring vasoconstriction and indirectly by favoring systemic humoral activation leading to higher catecholamine concentrations. It therefore appears logical that interventions that specifically downmodulate the sympathetic system would effectively relieve angina. However, due to the lack of appropriate studies, cardiac sympathectomy is not regularly performed in cardiology and its use remains largely empirical.
Stellate Ganglion Blockade
The left stellate (cervicothoracic) sympathetic ganglion is a point of convergence for sympathetic fibers before they synapse to the intermediolateral gray column in the thoracic spinal cord. Neuroanatomy provides compelling arguments in favor of stellate ganglion blockades to relieve angina, yet the evidence to support this practice is lacking.
The left stellate ganglion is typically located between the carotid artery and the cricoid cartilage at the level of C6, although anatomic variants and right-sided duplicity are possible. The left stellate ganglion can be safely accessed under ultrasound guidance and injected with various anesthetic substances to temporarily block (in theory) the transmission of nociceptive afference signals to the brain. In a case series of 59 consecutive patients, the mean period for angina relief was 3.5 weeks with stellate ganglion blockades with 15 mL of 0.5% bupivacaine, compared to 2.80 weeks for paravertebral blockades. These procedures could be performed serially with complication rates of approximately 3% (mostly reversible episodes of vertigo and hypotension, but also hematoma). The Horner syndrome is also another complication described as a result of the intervention. Permanent effects have been described with the direct ablation of the stellate ganglion using radiofrequency for angina, and other complex regional pain syndromes.
High Thoracic Epidural Analgesia
In a case series of 152 consecutive patients with refractory angina, serial epidural analgesia with bupivacaine through a permanent epidural catheter inserted at thoracic level 2 to 5 was associated with improved angina symptoms and quality of life for up to 6 years. Whereas there were no central nervous system infections, some patients developed cutaneous infection, a temporary drop in BP, and Horner syndrome.
Surgical Thoracic Sympathectomy
Surgical thoracic sympathectomy is a historic intervention that has been anecdotally used in refractory angina with varying success rates despite permanent sequelae. If considered, surgical thoracic sympathectomy should be preceded by temporary sympathetic blockade to establish the suspected contribution of sympathetic mediation to the cardiac pain.
Imipramine
Imipramine is a tricyclic antidepressant that has been tested in a small, randomized, cross-over, placebo-controlled trial in patients (predominantly female) with normal coronary angiogram, negative ergonovine provocation test, and prominent cardiac pain, despite previous attempt of β-blockers, CCBs, or long-acting nitrates. Unlike any other medications given to treat angina related to myocardial ischemia, imipramine was shown to reduce the sensitivity to cardiac pain triggered by either right ventricle (RV) pacing or IC adenosine (2.2 mg/min for 2 min). Patients treated with imipramine (50 mg nightly for 3 weeks) not only experienced a reduction in their angina count compared to placebo (–52% ± 25% vs. –1% ± 86%, p = 0.03) but were also more likely to report an improvement of their repeated RV pacing/IC adenosine cardiac pain sensitivity tests (60% vs. 12.5%, p = 0.01). These findings were confirmed by a group of independent investigators, who also reported a lack of efficacy on quality of life, likely due to the high incidence of side effects (mostly anticholinergic) associated with imipramine. Despite its unique effect on cardiac sensitivity, imipramine remains inadequately studied in patients with advanced CAD and refractory angina. The drug should probably be reserved for patients with a prominent neurogenic component to their angina, such as patients with sensitive heart syndrome.
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